The present invention is concerned with 2,4-disubstituted triazine derivatives having HIV replication inhibiting properties. The invention further relates to methods for their preparation and pharmaceutical compositions comprising them. The invention also relates to the use of said compounds in ihe manufacture of a medicament useful for the treatment of subjects suffering from HV (Human Immunodeficiency Virus) infection.
EP-0,834,507 discloses substituted diamino 1,3,5-triazine derivatives having HIV replication inhibiting properties. The present compounds differ from the known 1,3,5-triazines by structure and by their improved HIV replication inhibiting properties.
The present invention concerns the use of the compounds of formula 
the N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein
xe2x80x94a1xe2x95x90a2xe2x80x94a3xe2x95x90a4xe2x80x94 represents a bivalent radical of formula
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-1);
xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-2);
xe2x80x94Nxe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-3);
xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90Nxe2x80x94xe2x80x83xe2x80x83(a-4);
xe2x80x94Nxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-5);
n is 0, 1, 2, 3 or 4; and in case xe2x80x94a1xe2x95x90a2xe2x80x94a3xe2x95x90a4xe2x80x94 is (a-1), then n may also be 5;
R1 is hydrogen, aryl, formyl, C1-6alkylcarbonyl, C1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkyl substituted with formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl; and
each R2 independently is hydroxy, halo, C1-6alkyl optionally substituted with cyano or xe2x80x94C(xe2x95x90O)R4, C3-7cycloalkyl, C2-6alkenyl optionally substituted with one or more halogen atoms or cyano, C2-6alkynyl optionally substituted with one or more halogen atoms or cyano, C1-6alkyloxy, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, xe2x80x94S(xe2x95x90O)pR4, xe2x80x94NHxe2x80x94S(xe2x95x90O)R4, xe2x80x94C(xe2x95x90O)R4, xe2x80x94NHC(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)NHNH2, xe2x80x94NHC(xe2x95x90O)R4, xe2x80x94C(xe2x95x90NH)R4 or a radical of formula 
wherein
each A independently is N, CH or CR4;
B is NH, O, S or NR4;
p is 1 or 2; and
R4 is methyl, amino, mono- or dimethylamino or polyhalomethyl;
L is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-7cycloalkyl, whereby each of said aliphatic group may be substituted with one or two substituents independently selected from
C3-7cycloalkyl,
indolyl or isoindolyl, each optionally substituted with one, two, three or four substituents each independently selected from halo, C1-6alkyl, hydroxy, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, polyhalomethyl, polyhalomethyloxy and C1-6alkylcarbonyl,
phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R2; or
L is xe2x80x94Xxe2x80x94R3 wherein
R3 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R2; and
X is xe2x80x94NR1xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CHOHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94 or xe2x80x94S(xe2x95x90O)2xe2x80x94;
aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl and polyhaloC1-6alkyloxy;
for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection.
This invention also concerns compounds of formula (Ixe2x80x2) which are defined as compounds of formula (I) wherein the compounds cited in the following references
Recl. Trav. Chim. Pays-Bas (1969), 88(4), 426-38.
Polym. J. (Tokyo) (1996), 28(4), 337-42.
J. Inst. Chem. (India) (1978), 50(5), 213-14.
Nippon Kagaku Kaishi (1977), Issue 4, 549-55.
Kobunshi Kagaku (1973), 30(12), 720-6.
SU 189438
DE 2226474
are excluded;
i.e. compounds of formula 
the N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein the substituents are as defined under formula (I); with the proviso that compounds wherein
L is C1-3alkyl; R1 is selected from hydrogen, ethyl and methyl; xe2x80x94a1xe2x95x90a2xe2x80x94a3xe2x95x90a4xe2x80x94 represents a bivalent radical of formula (a-1); n is 0 or 1 and R2 is selected from fluoro, chloro, methyl, trifluoromethyl, ethyloxy and nitro; or
L is xe2x80x94Xxe2x80x94R3, X is xe2x80x94NHxe2x80x94; R1 is hydrogen; xe2x80x94a1xe2x95x90a2xe2x80x94a3xe2x95x90a4xe2x80x94 represents a bivalent radical of formula (a-1); n is 0 or 1 and R2 is selected from chloro, methyl, methyloxy, cyano, amino and nitro and R3 is phenyl, optionally substituted with one substituent selected from chloro, methyl, methyloxy, cyano, amino and nitro;
and the compounds
N,Nxe2x80x2-dipyridinyl-(1,3,5)-triazine-2,4-diamine;
(4-chloro-phenyl)-(4(1-(4-isobutyl-phenyl)-ethyl)-(1,3,5) triazin-2-yl)-amine
are not included.
A special group of compounds are compounds of formula (Ixe2x80x2), the N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein
xe2x80x94a1xe2x95x90a2xe2x80x94a3xe2x95x90a4xe2x80x94 represents a bivalent radical of formula
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-1);
xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-2);
xe2x80x94Nxe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-3);
xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90Nxe2x80x94xe2x80x83xe2x80x83(a-4);
xe2x80x94Nxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-5);
n is 0, 1, 2, 3 or 4; and in case xe2x80x94a1xe2x95x90a2xe2x80x94a3xe2x95x90a4xe2x80x94 is (a-1), then n may also be 5;
R1 is hydrogen, aryl, formyl, C1-6alkylcarbonyl, C1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkyl substituted with formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl; and
each R2 independently is hydroxy, halo, C1-6alkyl optionally substituted with cyano or xe2x80x94C(xe2x95x90O)R4, C3-7cycloalkyl, C2-6alkenyl optionally substituted with one or more halogen atoms or cyano, C2-6alkynyl optionally substituted with one or more halogen atoms or cyano, C1-6alkyloxy, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, xe2x80x94S(xe2x95x90O)pR4, xe2x80x94NHxe2x80x94S(xe2x95x90O)pR4, xe2x80x94C(xe2x95x90O)R4, xe2x80x94NHC(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)NHNH2, xe2x80x94NHC(xe2x95x90O)R4, xe2x80x94C(xe2x95x90NH)R4 or a radical of formula 
wherein
each A independently is N, CH or CR4;
B is NH, O, S or NR4;
p is 1 or 2; and
R4 is methyl, amino, mono- or dimethylamino or polyhalomethyl;
L is C4-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-7cycloalkyl, whereby each of said aliphatic group may be substituted with one or two substituents independently selected from
C3-7cycloalkyl,
indolyl or isoindolyl, each optionally substituted with one, two, three or four substituents each independently selected from halo, C1-6alkyl, hydroxy, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, polyhalomethyl, polyhalomethyloxy and C1-6alkylcarbonyl,
phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R2; or
L is xe2x80x94Xxe2x80x94R3 wherein
R3 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with two, three, four or five substituents each independently selected from the substituents defined in R2; and
X is xe2x80x94NR1xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CHOHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94 or xe2x80x94S(xe2x95x90O)2xe2x80x94;
aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl and polyhaloC1-6alkyloxy;
and suitably N,Nxe2x80x2-dipyridinyl-(1,3,5)-triazine-2,4-diamine is excluded.
Another special group of compounds are those compounds having the formula 
the N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein
xe2x80x94b1xe2x95x90b2xe2x80x94C(R2a)xe2x95x90b3xe2x80x94b4xe2x95x90 represents a bivalent radical of formula
xe2x80x94CHxe2x95x90CHxe2x80x94C(R2a)xe2x95x90CHxe2x80x94CHxe2x95x90xe2x80x83xe2x80x83(b-1);
xe2x80x94Nxe2x95x90CHxe2x80x94C(R2a)xe2x95x90CHxe2x80x94CHxe2x95x90xe2x80x83xe2x80x83(b-2);
xe2x80x94CHxe2x95x90Nxe2x80x94C(R2a)xe2x95x90CHxe2x80x94CHxe2x95x90xe2x80x83xe2x80x83(b-3);
xe2x80x83xe2x80x94Nxe2x95x90CHxe2x80x94C(R2a)xe2x95x90Nxe2x80x94CHxe2x95x90xe2x80x83xe2x80x83(b-4);
xe2x80x94Nxe2x95x90CHxe2x80x94C(R2a)xe2x95x90CHxe2x80x94Nxe2x95x90xe2x80x83xe2x80x83(b-5);
xe2x80x94CHxe2x95x90Nxe2x80x94C(R2a)xe2x95x90Nxe2x80x94CHxe2x95x90xe2x80x83xe2x80x83(b-6);
xe2x80x94Nxe2x95x90Nxe2x80x94C(R2a)xe2x95x90CHxe2x80x94CHxe2x95x90xe2x80x83xe2x80x83(b-7);
q is 0, 1, 2; or where possible q is 3 or 4;
R1 is hydrogen, aryl, formyl, C1-6alkylcarbonyl, C1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkyl substituted with formyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl;
R2a is cyano; aminocarbonyl; mono- or di(methyl)aminocarbonyl; C1-6alkyl substituted with cyano, aminocarbonyl or mono- or di(methyl)aminocarbonyl; C2-6alkenyl substituted with cyano; or C2-6alkynyl substituted with cyano;
each R2 independently is hydroxy, halo, C1-6alkyl optionally substituted with cyano or xe2x80x94C(xe2x95x90O)R4, C3-7cycloalkyl, C2-6alkenyl optionally substituted with one or more halogen atoms or cyano, C2-6alkynyl optionally substituted with one or more halogen atoms or cyano, C1-6alkyloxy, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, xe2x80x94S(xe2x95x90O)pR4, xe2x80x94NHxe2x80x94S(xe2x95x90O)pR4, xe2x80x94C(xe2x95x90O)R4, xe2x80x94NHC(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)NHNH2, xe2x80x94NHC(xe2x95x90O)R4, xe2x80x94C(xe2x95x90NH)R4 or a radical of formula 
wherein
each A independently is N, CH or CR4;
B is NH, O, S or NR4;
p is 1 or 2; and
R6 is methyl, amino, mono- or dimethylamino or polyhalomethyl;
L is C4-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-7cycloalkyl, whereby each of said aliphatic group may be substituted with one or two substituents independently selected from
C3-7cycloalkyl,
indolyl or isoindolyl, each optionally substituted with one, two, three or four substituents each independently selected from halo, C1-6alkyl, hydroxy, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, polyhalomethyl, polyhalomethyloxy and C1-6alkylcarbonyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R2; or
L is xe2x80x94Xxe2x80x94R3 wherein
R3 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with two, three, four or five substituents each independently selected from the substituents defined in R2; and
X is xe2x80x94NR1xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CHOHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94 or xe2x80x94S(xe2x95x90O)2xe2x80x94;
aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxy, cyano, nitro, polyhaloC1-6alkyl and polyhaloC1-6alkyloxy;
and suitably N,Nxe2x80x2-dipyridinyl-(1,3,5)-triazine-2,4-diamine is excluded.
Said special groups of compounds are deemed novel and can be used as a medicine.
The present invention also relates to a method of treating warm-blooded animals suffering from HIV (Human Immunodeficiency Virus) infection. Said method comprises the administration of a therapeutically effective amount of a compound of formula (I), (Ixe2x80x2) or (I-a) or a N-oxide form, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof in admixture with a pharmaceutical carrier.
As used in the foregoing definitions and hereinafter C1-3alkyl as a group or part of a group encompasses the straight and branched chain saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as, methyl, ethyl and propyl; C1-4alkyl encompasses the straight and branched chain saturated hydrocarbon radicals as defined in C1-3alkyl as well as butyl; C1-6alkyl encompasses the straight and branched chain saturated hydrocarbon radicals as defined in C1-4alkyl as well as the higher homologues thereof containing 5 to 6 carbon atoms such as pentyl, hexyl, 2-methylbutyl and the like; C1-10alkyl encompasses the straight and branched chain saturated hydrocarbon radicals as defined in C1-6alkyl as well as the higher homologues thereof containing 7 to 10 carbon atoms such as heptyl, octyl, nonyl or decyl; C4-10alkyl encompasses the straight and branched chain saturated hydrocarbon radicals as defined above, having from 4 to 10 carbon atoms; C3-7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C2-6alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, 2-ethenyl, 2-propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl and the like; C2-10alkenyl encompasses the straight and branched chain hydrocarbon radicals as defined in C2-6alkenyl as well as the higher homologues thereof containing 7 to 10 carbon atoms such as 3-heptenyl, 2-octenyl, 2-nonenyl, 2-decenyl and the like, whereby the carbon atom attached to the triazine ring is preferably an aliphatic carbon atom; C2-6alkynyl defines straight and branched chain hydrocarbon, radicals containing one triple bond and having from 2 to 6 carbon atoms such as, 2-ethynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl, 3-hexynyl and the like; C2-10alkynyl encompasses the straight and branched chain hydrocarbon radicals as defined in C2-6alkynyl as well as the higher homologues thereof containing 7 to 10 carbon atoms such as 3-heptynyl, 2-octynyl, 2-nonynyl, 2-decynyl and the like, whereby the carbon atom attached to the triazine ring is preferably an aliphatic carbon atom. The term C1-6alkyloxy defines straight or branched chain saturated hydrocarbon radicals such as methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, 1-methylethyloxy, 2-methylpropyloxy, 2-methylbutyloxy and the like; C3-6cycloalkyloxy is generic to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
As used herein before, the term (xe2x95x90O) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide group when attached once to a sulfur atom, and a sulfonyl group when attached twice to a sulfur atom.
The term halo is generic to fluoro, chloro, bromo and iodo. As used in the foregoing and hereinafter, polyhalomethyl as a group or part of a group is defined as mono- or polyhalosubstituted methyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl; polyhaloC1-6alkyl as a group or part of a group is defined as mono- or polyhalosubstituted C1-6alkyl, for example, the groups defined in halomethyl, 1,1-difluoro-ethyl and the like. In case more than one halogen atoms are attached to an alkyl group within the definition of polyhalomethyl or polyhaloC1-6alkyl, they may be the same or different.
For therapeutic use, salts of the compounds of formula (I), (Ixe2x80x2) or (I-a) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I), (Ixe2x80x2) or (I-a) are able to form. The compounds of formula (I), (Ixe2x80x2) or (I-a) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.
The compounds of formula (I), (Ixe2x80x2) or (I-a) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
The term addition salts also comprises the hydrates and the solvent addition forms which the compounds of formula (I), (Ixe2x80x2) or (I-a) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
It will be appreciated that some of the compounds of formula (I), (Ixe2x80x2) or (I-a) and their N-oxides, addition salts, quaternary amines and stereochemically isomeric forms may contain one or more centers of chirality and exist as stereochemically isomeric forms.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible stereoisomeric forms which the compounds of formula (I), (Ixe2x80x2) or (I-a) and their N-oxides, addition salts, quaternary amines or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I), (Ixe2x80x2) or (I-a) and their N-oxides, addition salts or quaternary amines substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. In particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E- or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of formula (I), (Ixe2x80x2) or (I-a) are obviously intended to be embraced within the scope of this invention.
Some of the compounds of formula (I), (Ixe2x80x2) or (I-a) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Lines drawn into ring systems from substituents indicate that the bond may be attached to any of the suitable ring atoms.
When any variable (e.g. R2) occurs more than one time in any constituent, each definition is independent.
Whenever used hereinafter, the term xe2x80x9ccompounds of formula (I)xe2x80x9d, xe2x80x9ccompounds of formula (Ixe2x80x2)xe2x80x9d, or xe2x80x9ccompounds of formula (I-a)xe2x80x9d is meant to include also the N-oxides, the addition salts, the quaternary amines and all stereoisomeric forms.
An interesting group of compounds are those compounds of formula (I) or (Ixe2x80x2) wherein one or more of the following conditions are met:
(i) n is 1;
(ii) xe2x80x94a1xe2x95x90a2xe2x80x94a3xe2x95x90a4xe2x80x94 represents a bivalent radical of formula (a-1);
(iii) R1 is hydrogen or alkyl;
(iv) R2 is cyano; aminocarbonyl; mono- or di(methyl)aminocarbonyl; C1-6alkyl substituted with cyano, aminocarbonyl or mono- or di(methyl)aminocarbonyl; and more in particular, R2 is on the 4 position relative to the xe2x80x94NR1xe2x80x94 moiety;
i) L is xe2x80x94Xxe2x80x94R3 wherein X is preferably xe2x80x94NR1xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, most preferably X is xe2x80x94NHxe2x80x94, and R3 is substituted phenyl with C1-6alkyl, halogen and cyano as preferred substituents.
Another interesting group of compounds contains those compounds of formula (I-a) wherein one or more of the following restrictions apply:
i) xe2x80x94b1xe2x95x90b2xe2x80x94C(R2a)xe2x95x90b3xe2x80x94b4xe2x95x90 is a radical of formula (b-1);
ii) q is 0;
iii) R2a is cyano; aminocarbonyl; mono- or di(methyl)aminocarbonyl; C1-6alkyl substituted with cyano, aminocarbonyl or mono- or di(methyl)aminocarbonyl, preferably R2a is cyano;
iv) L is xe2x80x94Xxe2x80x94R3 wherein X is preferably xe2x80x94NR1xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, most preferably X is xe2x80x94NHxe2x80x94, and R3 is substituted phenyl with C1-6alkyl, halogen and cyano as preferred substituents.
Preferred compounds are those compounds of formula (Ixe2x80x2) or (I-a) wherein L is xe2x80x94Xxe2x80x94R3 wherein R3 is a disubstituted phenyl group or a trisubstituted phenyl group, each substituent independently selected from chloro, bromo, fluoro, cyano or C1-4alkyl.
Compounds of formula (Ixe2x80x2) wherein L is a radical of formula xe2x80x94Xxe2x80x94R3, said compounds are represented by formula (Ixe2x80x2-a), can be prepared by reacting an intermediate of formula (II) wherein W1 is a suitable leaving group, for example, a halogen, with an amine derivative of formula (III) in a reaction-inert solvent, for example, tetrahydrofuran, 1,4-dioxane or the like, in the presence of a suitable base such as, triethylamine; and subsequently reacting the thus obtained intermediate of formula (IV) with an intermediate of formula (V) in a reaction-inert solvent such as acetonitrile, 1,4-dioxane or the like, in the presence of a base such as potassium carbonate, sodium hydride, N,N-diisopropyl-ethylamine or the like. 
The order of the above reaction scheme may also be reversed, i.e. first an intermediate of formula (II) may be reacted with an intermediate of formula (V), and then, the resulting intermediate may further be reacted with an amine derivative of formula (III); thus forming a compound of formula (Ixe2x80x2-a).
The reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, extraction, crystallization, distillation, trituration and chromatography.
Compounds of formula (Ixe2x80x2) wherein L is an optionally substituted C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-7cycloalkyl, said L being represented by La and said compounds being represented by formula (Ixe2x80x2-b), can be prepared by first making a Grignard reagent of an intermediate of formula (VI) wherein W2 is a suitable leaving group such as, a halogen, e.g. bromine, in the presence of magnesium in a reaction-inert solvent such as, diethyl ether, and subsequently reacting said Grignard reagent with an intermediate of formula (VII) wherein W1 is a suitable leaving group such as, a halogen, e.g. chlorine, in a reaction-inert solvent, for example, benzene, thus forming an intermediate of formula (VIII). It may be convenient to perform the above reaction under an inert atmosphere, for instance, argon. Intermediate (VIII) may be isolated from its reaction medium, or may be in situ further reacted with an intermediate of formula (III) in a reaction-inert solvent such as, 1,4-dioxane, and in the presence of a suitable base such as, diisopropylethylamine or the like, thus forming a compound of formula (Ixe2x80x2-b). 
The compounds of formula (Ixe2x80x2) may further be prepared by converting compounds of formula (Ixe2x80x2) into each other according to art-known group transformation reactions.
The compounds of formula (Ixe2x80x2) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (Ixe2x80x2) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t.butyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Some of the intermediates as mentioned hereinabove are commercially available or can be prepared according to art-known procedures.
Compounds of formula (Ixe2x80x2) and some of the intermediates may have one or more stereogenic centers in their structure, present in a R or a S configuration.
The compounds of formula (Ixe2x80x2) as prepared in the hereinabove described processes may be synthesized as a mixture of stereoisomeric forms, in particular in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (Ixe2x80x2) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (Ixe2x80x2) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
It will be appreciated by those skilled in the art that in the processes described above the functional groups of intermediate compounds may need to be blocked by protecting groups.
Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C1-6alkyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after a reaction step.
The use of protecting groups is fully described in xe2x80x98Protective Groups in Organic Chemistryxe2x80x99, edited by J W F McOmie, Plenum Press (1973), and xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 2nd edition, T W Greene and P G M Wutz, Wiley Interscience (1991).
The compounds of formula (I), (Ixe2x80x2) and (I-a) show antiretroviral properties, in particular against Human Immunodeficiency Virus (HIV), which is the aetiological agent of Acquired Immune Deficiency Syndrome (AIDS) in humans. The HV virus preferentially infects human T-4 cells and destroys them or changes their normal function, particularly the coordination of the immune system. As a result, an infected patient has an everdecreasing number of T-4 cells, which moreover behave abnormally. Hence, the immunological defense system is unable to combat infections and neoplasms and the HIV infected subject usually dies by opportunistic infections such as pneumonia, or by cancers. Other conditions associated with HIV infection include thrombocytopaenia, Kaposi""s sarcoma and infection of the central nervous system characterized by progressive demyelination, resulting in dementia and symptoms such as, progressive dysarthria, ataxia and disorientation. HIV infection further has also been associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL) and AIDS-related complex (ARC).
The present compounds also show activity against HIV-1 strains that have acquired resistance to art-known non-nucleoside reverse transcriptase inhibitors. They also have little or no binding affinity to human xcex1-1 acid glycoprotein.
Due to their antiretroviral properties, particularly their anti-HIV properties, especially their anti-HIV-1-activity, the compounds of formula (I), (Ixe2x80x2) or (I-a), their N-oxides, addition salts and stereochemically isomeric forms, are useful in the treatment of individuals infected by HIV and for the prophylaxis of these infections. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses whose existence is mediated by, or depends upon, the enzyme reverse transcriptase. Conditions which may be prevented or treated with the compounds of the present invention, especially conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as, for example HIV mediated dementia and multiple sclerosis.
The compounds of the present invention or any subgroup thereof may therefore be used as medicines against above-mentioned conditions. Said use as a medicine or method of treatment comprises the systemic administration to HIV-infected subjects of an amount effective to combat the conditions associated with HIV and other pathogenic retroviruses, especially HIV-1.
The compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
Apart from their pharmacological properties, some of the compounds of formula (Ixe2x80x2) have interesting physicochemical properties. For instance, they have good solubility. To aid solubility of the less soluble compounds of formula (Ixe2x80x2), suitable ingredients, e.g. cyclodextrins, may be included in the compositions. Appropriate cyclodextrins are xcex1-, xcex2-, xcex3-cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C1-6alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated xcex2-CD; hydroxyC1-6alkyl, particularly hydroxyethyl, hydroxy-propyl or hydroxybutyl; carboxyC1-6alkyl, particularly carboxymethyl or carboxy-ethyl; C1-6alkylcarbonyl, particularly acetyl. Especially noteworthy as complexants and/or solubilizers are xcex2-CD, randomly methylated xcex2-CD, 2,6-dimethyl-xcex3-CD, 2-hydroxyethyl-xcex2-CD, 2-hydroxyethyl-xcex3-CD, 2-hydroxypropyl-xcex3-CD and (2-carboxymethoxy)propyl-xcex2-CD, and in particular 2-hydroxypropyl-xcex2-CD (2-HP-xcex2-CD).
The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy-propyl and hydroxyethyl.
The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The average substitution degree (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit. The M.S. and D.S. value can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for one given cyclodextrin derivative. Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125 to 10 and the D.S. ranges from 0.125 to 3.
Other suitable compositions for oral or rectal administration comprise particles obtainable by melt-extruding a mixture comprising a compound of formula (Ixe2x80x2) and an appropriate water-soluble polymer and subsequently milling said melt-extruded mixture. Said particles can then be formulated by conventional techniques into pharmaceutical dosage forms such as tablets and capsules.
Said particles consist of a solid dispersion comprising a compound of formula (Ixe2x80x2) and one or more pharmaceutically acceptable water-soluble polymers. The preferred technique for preparing solid dispersions is the melt-extrusion process comprising the following steps:
a) mixing a compound of formula (Ixe2x80x2) and an appropriate water-soluble polymer,
b) optionally blending additives with the thus obtained mixture,
c) heating the thus obtained blend until one obtains a homogenous melt,
d) forcing the thus obtained melt through one or more nozzles; and
e) cooling the melt till it solidifies.
The solid dispersion product is milled or ground to particles having a particle size of less than 600 xcexcm, preferably less than 400 xcexcm and most preferably less than 125 xcexcm.
The water-soluble polymers in the particles are polymers that have an apparent viscosity, when dissolved at 20xc2x0 C. in an aqueous solution at 2% (w/v), of 1 to 5000 mPa.s, more preferably of 1 to 700 mPa.s, and most preferred of 1 to 100 mPa.s. For example, suitable water-soluble polymers include alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkyl alkylcelluloses, carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, starches, pectines, chitin derivates, polysaccharides, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts and esters thereof, methacrylate copolymers, polyvinylalcohol, polyalkylene oxides and copolymers of ethylene oxide and propylene oxide. Preferred water-soluble polymers are Eudragit E(copyright) (Rxc3x6hm GmbH, Germany) and hydroxypropyl methylcelluloses.
Also one or more cyclodextrins can be used as water soluble polymer in the preparation of the above-mentioned particles as is disclosed in WO 97/18839. Said cyclodextrins include the pharmaceutically acceptable unsubstituted and substituted cyclodextrins known in the art, more particularly xcex1, xcex2 or xcex3 cyclodextrins or the pharmaceutically acceptable derivatives thereof.
Substituted cyclodextrins which can be used include polyethers described in U.S. Pat. No. 3,459,731. Further substituted cyclodextrins are ethers wherein the hydrogen of one or more cyclodextrin hydroxy groups is replaced by C1-6alkyl, hydroxyC1-6alkyl, carboxy-C1-6alkyl or C1-6alkyloxycarbonylC1-6alkyl or mixed ethers thereof. In particular such substituted cyclodextrins are ethers wherein the hydrogen of one or more cyclodextrin hydroxy-groups is replaced by C1-3alkyl, hydroxyC2-4alkyl or carboxyC1-2alkyl or more in particular by methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxy-methyl or carboxyethyl.
Of particular utility are the xcex2-cyclodextrin ethers, e.g. dimethyl-xcex2-cyclodextrin as described in Drugs of the Future, Vol. 9, No. 8, p. 577-578 by M. Nogradi (1984) and polyethers, e.g. hydroxypropyl xcex2-cyclodextrin and hydroxyethyl xcex2-cyclodextrin, being examples. Such an alkyl ether may be a methyl ether with a degree of substitution of about 0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropyl cyclodextrin may for example be formed from the reaction between xcex2-cyclodextrin an propylene oxide and may have a MS value of about 0.125 to 10, e.g. about 0.3 to 3.
A more novel type of substituted cyclodextrins is sulfobutylcyclodextrines.
The ratio of compound of formula (Ixe2x80x2) over cyclodextrin may vary widely. For example ratios of 1/100 to 100/1 may be applied. Interesting ratios of compound of formula (Ixe2x80x2) over cyclodextrin range from about 1/10 to 10/1. More interesting ratios range from about 1/5 to 5/1.
It may further be convenient to formulate the compounds of formula (Ixe2x80x2) in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Useful surface modifiers are believed to include those which physically adhere to the surface of the compound of formula (Ixe2x80x2) but do not chemically bond to said compound.
Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.
Yet another interesting way of formulating the compounds of formula (Ixe2x80x2) involves a pharmaceutical composition whereby the compounds of formula (Ixe2x80x2) are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration.
Said beads, comprise a central, rounded or spherical core, a coating film of a hydrophilic polymer and a compound of formula (Ixe2x80x2) and a seal-coating polymer layer.
Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
Those of skill in the treatment of HIV-infection could determine the effective daily amount from the test results presented here. In general it is contemplated that an effective daily amount,would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
The exact dosage and frequency of administration depends on the particular compound of formula (I), (Ixe2x80x2) or (I-a) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines and are not intended to limit the scope or use of the invention to any extent.
Also, the combination of an antiretroviral compound and a compound of formula (I), (Ixe2x80x2) or (I-a) can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of formula (I), (Ixe2x80x2), or (I-a) and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. Said other antiretroviral compounds may be known antiretroviral compounds such as nucleoside reverse transcriptase inhibitors, e.g. zidovudine (3xe2x80x2-azido-3xe2x80x2-deoxythymidine, AZT), didanosine (dideoxy inosine; ddI), zalcitabine (dideoxycytidine, ddC) or lamivudine (3xe2x80x2-thia-2xe2x80x2-3xe2x80x2-dideoxycytidine, 3TC) and the like; non-nucleoside reverse transciptase inhibitors such as suramine, pentamidine, thymopentin, castanospermine, efavirenz, dextran (dextran sulfate), foscarnet-sodium (trisodium phosphono fornate), nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b: 2xe2x80x2,3xe2x80x2-e][1,4]diazepin-6-one), tacrine (tetrahydroaminoacridine) and the like; compounds of the TIBO (tetrahydroimidazo-[4,5,1-jk] [1,4]-benzodiazepine-2(1H)-one and thione)-type e.g. (S)-8-chloro4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione; compounds of the xcex1-APA (xcex1-anilino phenyl acetamide) type e.g. xcex1-[(2-nitrophenyl)amino]-2,6-dichlorobenzene-acetamide and the like; TAT-inhibitors, e.g. RO-5-3335 and the like; protease inhibitors e.g. indinavir, ritanovir, saquinovir, ABT-378 and the like; or immunomodulating agents, e.g. levamisole and the like. The compound of formula (I), (Ixe2x80x2) or (I-a) can also be combined with another compound of formula (I), (Ixe2x80x2) or (I-a).